Leishmaniasis has been the cause of great suffering and
death for hundreds of years.

Representations of skin lesions and facial deformities have been found on
pre-Inca

pottery from Peru and Ecuador dating back to the first century AD. They
are evidence

that some forms of leishmaniasis prevailed as early as this period. The
discovery of parasites in lesions of cutaneous or visceral leishmaniasis was
reported in the late 1800s and early 1900s

.

1756;Russel:The
first description in English

1898;Borovsky
noted the protozoal nature of the organism

1903;Leishman
identified the parasite

1903;Donovan
described identical organisms in a splenic puncture

Etiology

Leishmaniasis is the result of infection with intracellular protozoan
parasites belonging to the genus Leishmania. The organisms are found in
two morphologic forms during their life cycle. In humans and other mammalian
hosts, they exist within macrophages as round to oval nonflagellated amastigotes
and in the arthropod vectors (sandflies) the parasites exist as elongated
flagellated promastigotes

About 30 species of sandflies can become infected when taking a blood meal
from a reservoir host. In the old world genus Phlebotomus and in the new
world genus Lutzomia are responsible for transmitting the disease.
Sandflies are small mosquito-like insects 1.5 to 4 mm in length and their small
size allows them to pass through ordinary mesh screens and mosquito netting.

Hosts are infected humans, wild animals, such as rodents, and domestic
animals, such as dogs. Most leishmaniases are zoonotic (transmitted to humans
from animals), and humans become infected only when accidentally exposed to the
natural transmission cycle. However, in the anthroponotic forms (those
transmitted from human to human through the sandfly vector), humans are the sole
reservoir host.

Classification

Leishmaniasis presents itself in humans in four different forms with a broad
range of clinical manifestations. All forms can have devastating consequences.
Similar to Hansen disease, leishmaniasis is a disease in which the clinical
diversity reflects a complex interplay between the virulence of the infecting
species and the host's immune response. At one extreme, localized cutaneous
disease demonstrates a vigorous immune response, with most cases resolving
without intervention. This form of disease exhibits a helper T-cell subtype 1
(TH1) immune response, with interleukin 2, interferon g, and interleukin 12 as
the prominent cytokines that induce disease resolution. At the other extreme,
with visceral or diffuse cutaneous disease, patients exhibit relative anergy to
the Leishmania organism and have a prominent helper T-cell subtype 2(TH2)
cytokine profile.

Visceral leishmaniasis (VL),
also known as kala azar, is the most severe form of the disease, which,
if untreated, has a mortality rate of almost 100%. It is characterized by
irregular bouts of fever, substantial weight loss, swelling of the spleen and
liver, and anaemia.

Mucocutaneous leishmaniasis (MCL),
or espundia, produces lesions which can lead to extensive and disfiguring
destruction of mucous membranes of the nose, mouth and throat cavities.

Cutaneous leishmaniasis (CL)
can produce large numbers of skin ulcers—as many as 200 in some cases—on the
exposed parts of the body, such as the face, arms and legs, causing serious
disability and leaving the patient permanently scarred. Diffuse cutaneous
leishmaniasis (DCL) never heals spontaneously and tends to relapse after
treatment. The cutaneous forms of leishmaniasis are the most common and
represent 50-75% of all new cases.

Epidemiology

Geographic Distribution

The leishmaniases are now endemic in 88 countries on five
continents—Africa, Asia, Europe, North America and South America—with a
total of 350 million people at risk.

It is believed that worldwide 12 million people are affected by
leishmaniasis; this figure includes cases with overt disease and those with
no apparent symptoms. Of the 1.5-2 million new cases of leishmaniasis
estimated to occur annually, only 600 000 are officially declared.

Of the 500 000 new cases of VL which occur annually, 90% are in five
countries: Bangladesh, Brazil, India, Nepal and Sudan.

90% of all cases of MCL occur in Bolivia, Brazil and Peru.

90% of all cases of CL occur in Afghanistan, Brazil, Iran, Peru,
Saudi Arabia and Syria, with 1-1.5 million new cases reported annually
worldwide.

In Iran, CL is endemic in south, east north and some part of the
center of Iran.

The geographical distribution of leishmaniasis is limited by the
distribution of the sandfly, its susceptibility to cold climates, its
tendency to take blood from humans or animals only and its capacity to
support the internal development of specific species of Leishmania.

Increased Prevalence

Since 1993, regions that are Leishmania-endemic have expanded
significantly, accompanied by a sharp increase in the number of recorded
cases of the disease.

The geographic spread is due to factors related mostly to
development. These include massive rural-urban migration and agro-industrial
projects that bring non-immune urban dwellers into endemic rural areas.
Man-made projects with environmental impact, like dams, irrigation systems
and wells, as well as deforestation, also contribute to the spread of
leishmaniasis.

AIDS and other immunosuppressive conditions increase the risk of Leishmania-infected
people developing visceral illness. In certain areas of the world the risk
of co-infection with HIV is rising due to epidemiological changes.

Leishmania/HIV
Co-infection

Leishmania/HIV
co-infection is emerging as an extremely serious, new disease and it is
increasingly frequent. Leishmania/HIV co-infections are considered a real
threat, especially in south-western Europe
where between 25% and 70% of adult VL cases are related to HIV

and where 1.5%to 9% of AIDS cases suffer form newly acquired or
reactivated VL.

Intravenous drug users have been identified as the main population at
risk.

It is anticipated that the
number of Leishmania/HIV co-infections will continue to rise in the
coming years and there are indications that cases are no longer restricted to
endemic areas. The overlapping geographical distribution of VL and AIDS is
increasing due to two main factors: the spread of the AIDS pandemic in suburban
and rural areas of the world, and the simultaneous spread of VL from rural to
suburban areas.There are important clinical, diagnostic, chemotherapeutic,
epidemiological and economic implications of this trend.

Although people are often bitten by sandflies infected with Leishmania
protozoa, most do not develop the disease. However, among persons who
are immunosuppressed (e.g. as a result of advanced HIV infections,
immunosuppressive treatment for organ transplants, haematological
malignancy, auto-immune diseases), cases quickly evolve to a full clinical
presentation of severe leishmaniasis.

AIDS and VL are locked in a vicious circle of mutual reinforcement.
On the one hand, VL quickly accelerates the onset of AIDS (with
opportunistic diseases such as tuberculosis or pneumonia) and shortens the
life expectancy of HIV-infected people. On the other hand, HIV spurs the
spread of VL. AIDS increases the risk of VL by 100-1000 times in endemic
areas.

This
duo of diseases produces cumulative deficiency of the immune response since Leishmania
parasites and HIV destroy the same cells, exponentially increasing disease
severity and consequences. VL is considered a major contributor to a fatal
outcome in co-infected patients. Lately, however, use of tritherapy, where it is
available, has improved the prognosis for Leishmania/HIV cases.

Leishmaniasis can be transmitted directly person to person through
the sharing of needles, as is often the case among intravenous drug users.
This group is the main population at risk for co-infection. Based on a study
done in Spain, Leishmania spp were detected by PCR technique, in 65
(52%) of 125 syringes collected in southern Madrid,in 1998, and in 52 (34%) of 154 collected in southwestern Madrid in
2000-01.

Specific Problems

Leishmania/HIV
co-infections impose specific difficulties in terms of diagnosis and
treatment. The usual clinical features (fever, weight loss, liver and spleen
enlargement, inflammation of the lymph nodes) are not always present.The
clinical diagnosis can also be made difficult by associated diseases such as
cryptosporidium, disseminated cryptococcosis, cytomegalovirusinfection
or mycobacterial infection.

The serological diagnosis is falsely negative in 42.6% of
co-infected patients. HIV-positive patients have difficulty in producing
antibodies against new infectious agents, especially at a late stage or
during relapses. Consequently, there is a need to use two or more
serological tests and antigens freshly prepared in the laboratory to
increase sensitivity.

Although multiple localizations are frequent (blood, skin, digestive
tract, lungs, central nervous system),parasitological diagnosis can
be difficult and has to be repeated to orient the treatment. Bone marrow
aspirate (BMA) remains the safest and most sensitive technique, but spleen
aspirate and liver biopsy are also used. When BMA cannot be performed, the
search for Leishmania can be conducted in peripheral blood samples.

Treatment for co-infected patients is aimed at clinical and
parasitological cures and prevention of relapses. Unfortunately, in such
patients treatment failure, relapses due to drug resistance and drug
toxicity are very common. In south-western Europe, follow-up studies using
pentavalent antimonials, the same first-line drug used to treat classic
leishmaniasis, show a positive response in 83% of cases. However, 52% of
patients relapse within a period of one month to three years, with the
number of relapses ranging from one to four.

The
main alternative drugs include pentamidine, amphotericin B and amphotericin B
encapsulated in liposomes. This encapsulation reduces the occurrence of
side-effects, but relapses still occur and the drug remains extremely expensive.

Epidemiological Changes

Leishmania/HIV
co-infections can lead to epidemiological changes which modify the
traditional patterns of zoonotic VL. Co-infected patients harbour a high
number of Leishmania in their blood so there is also a risk of them
becoming reservoirs of the disease (that is, infective for the sandfly
vector) as in anthroponotic foci in Bangladesh, India, Nepal and East
Africa. Consequently, there is an increased risk of future epidemics.

Experimentally, sandflies can be infected through a blood meal
containing a very small quantity of blood from co-infected patients. The
quantity may be less than the content of a needle. As 71.1% of co-infected
patients in south-western Europe are intravenous drug users, transmission of
Leishmania has occurred through the sharing of syringes in this
population group.

Clinical
Patterns

Old world cutaneous leishmaniasis
begins as a small erythematous papule, which may appear immediately after the
bite of the sandfly but usually appears 2 to 4 weeks later. One or more lesions
occur on unclothed part of the body. Lesions may be associated with
sporotrichotic spread and usually heal spontaneously. The sequence of nodule,
crusting, ulceration and healing with scar formation is common to all the
self-healing sores.

Recidivans cutaneous leishmaniasis
(RCL): A relatively uncommon
clinicalvariant of leishmaniasis, RCL presents as a recurrence of lesions at the
site of apparently healed disease years after the original infection.Typically,
RCL lesions occur on the face, and RCL presents as an enlarging papule, plaque,
or coalescence of papules that heals with central scarring. Relentless expansion
at the periphery may cause significant facial destruction similar to the lupus
vulgaris variant of cutaneous tuberculosis.

Post kala azar dermal
leishmaniasis (PKDL): Endemic
to India and the Sudan, this form of leishmaniasis develops months to years
after the patient’s recovery from visceral leishmaniasis. Cutaneous lesions
demonstrate great variability, ranging from hypopigmented macules to
erythematous papules and from nodules to plaques. As in leprosy, the wide
clinical spectrum of PKDL reflects the immune response of the individual to the
Leishmania organism. Lesions may be numerous and persist for decades. Isolated
parasites from the lesions are identical to those causing the original visceral
disease.

Diagnosis

Differential diagnosis of LCL is
extensive and includes impetigo, pyoderma gangrenosum, deep fungal infection,
mycobacterial infection, sarcoidosis, and squamous cell carcinoma. In the
endemic areas the clinical diagnosis is not difficult but the definite diagnosis
rests on finding parasites in the skin. Usually, making a smear of material from
the sore and staining it with Wright’s, Giemsa or Leishman’s stain on a
microscope slide best achieve this. In addition, Polymerase chain reaction (PCR)
is one of the newest techniques used to identify leishmaniasis and shows
significant promise as a method applicable for both detection and speciation.
Most research laboratories have reported higher sensitivity and specificity with
PCR than with other currently available diagnostic methods.

Treatment

The treatment of leishmaniasis
depends on the clinical form of the disease. For 50 years, the mainstay of
antileishmanial therapy has been pentavalentantimony (sodium stibogluconate or meglumine antimonate).

Other measures include freezing,
local heat, oral ketoconazole, rifampicin and topical paromomycin. Surgical
excision usually is not recommended because of the risk of relapse and cosmetic
disfigurement.

To date, no vaccines are available
commercially.

The World Health Organization Response

WHO has set the following objectives:

1. To provide early diagnosis
and prompt treatment;

2. To control the sandfly
population through residual insecticide spraying of houses

and through the use of insecticide-impregnated bed nets;

3. To provide health education
and produce training materials;

4. To detect and contain
epidemics in the early stages;

5. To provide early diagnosis
and effective management for Leishmania/HIV coinfections.

Because of the anticipated substantial
increase in Leishmania/HIV co-infections, they are among the priorities
for WHO's Department of Communicable Disease Surveillance and Response (CSR).

In 1996, WHO established an initial surveillance system, comprised
of 14 institutions in 10 countries. A standardized Case Report Form was
elaborated and endorsed by the members of the network, and a Central
International Registry was set up within WHO to centralize, process and
disseminate information on co-infections.

In 1998, a new WHO/Joint United Nations Programme on HIV/AIDS
(UNAIDS) initiative was launched which helped strengthen the surveillance
network; it has been expanded to include 28 institutions, especially in East
Africa and the Indian subcontinent (India, Nepal). All member institutions
of the network report to WHO on an annual basis. A computerized Geographic
Information System (GIS) is used to map and monitor co-infections in a way
that permits easy visualization and analysis of epidemiological data.

The evolution of Leishmania/HIV
co-infection is being closely monitored by extending the geographic coverage of
the surveillance network and by improving case reporting. WHO encourages active
medical surveillance, especially in south-western Europe, of intravenous drug
users, the main population at risk. Finally, because case notification of
leishmaniasis is compulsory in only 40 of the 88 endemic countries, WHO strongly
suggests the remaining 48 endemic countries follow suit.

Summery

Leishmaniasis
is a disease caused by protozoa, and it affects as many as 12 million people
worldwide, with 1.5-2 million new cases each year. Transmitted by the bite of a
sandfly, the clinical spectrum of leishmaniasis ranges from a self-resolving
cutaneous ulcer, to a mutilating mucocutaneous disease, to a fatal systemic
illness. The global incidence of this infectious disease has been increasing
during recent years because of increased international travel, human alteration
of vector habitats, and concomitant factors that result in increased
susceptibility such as HIV infection and malnutrition. Many Leishmania species
transmit the disease, and the clinical spectrum, although once believed to be
predictable, continues to evolve. Diagnosis may be difficult because of the
small size of the protozoa sequestered within macrophages of the skin, bone
marrow, and reticuloendothelial system. Therapy has long been a challenge for
the more severe forms of the disease and is made more difficult by the emergence
of drug resistance. Noeffective vaccine
is available for leishmaniasis.